Identification of structural determinants of ligand selectivity in 5-HT₂ receptor subtypes on the basis of protein-ligand interactions.

Drug selectivity is one of the most critical improvement steps in drug development. The 5-hydroxytryptamine 2 (5-HT₂) receptor has 3 subtypes that exhibit different pharmacological functions. Because of their high amino acid sequence similarity, designing small molecules that selectively activate only 1 receptor among the 3 subtypes is difficult. We performed homology modeling of the 5-HT₂ receptor subtypes using the β₂-adrenergic receptor as a template to identify differences in active sites that may influence 5-HT₂ receptor agonist selectivity. A subset of selective 5-HT₂ agonists was docked into the modeled protein structures to investigate their interactions with each receptor. Subtype-specific active site residues at positions xl2.54, 5.39, and 5.46 interacted differently with each ligand. Molecular dynamics simulations revealed that position 5.46 of the 5-HT(2A) receptor interacted more favorably with selective 5-HT(2A) agonists than with selective 5-HT(2B) agonists. These computationally obtained insights provided clues to improving agonist selectivity for specific pharmacological action at 5-HT₂ receptors.